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PDBsum entry 3fmz
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Transport protein
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PDB id
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3fmz
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References listed in PDB file
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Key reference
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Title
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Identification and characterization of a non-Retinoid ligand for retinol-Binding protein 4 which lowers serum retinol-Binding protein 4 levels in vivo.
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Authors
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A.Motani,
Z.Wang,
M.Conn,
K.Siegler,
Y.Zhang,
Q.Liu,
S.Johnstone,
H.Xu,
S.Thibault,
Y.Wang,
P.Fan,
R.Connors,
H.Le,
G.Xu,
N.Walker,
B.Shan,
P.Coward.
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Ref.
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J Biol Chem, 2009,
284,
7673-7680.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Retinol-binding protein 4 (RBP4) transports retinol from the liver to
extrahepatic tissues, and RBP4 lowering is reported to improve insulin
sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm)
non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and
its binding partner transthyretin. Analysis of the RBP4-A1120 co-crystal
structure reveals that A1120 induces critical conformational changes at the
RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4
and retinol levels but, unexpectedly, does not improve insulin sensitivity. In
addition, we show that Rpb4(-/-) mice display normal insulin sensitivity and are
not protected from high fat diet-induced insulin resistance. We conclude that
lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore,
RBP4 lowering may not be an effective strategy for treating diabetes.
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Figure 1.
In vitro characterization of A1120. A, chemical structure of
A1120. B–D, representative radioligand binding isotherms for
human RBP4 (B), mouse RBP4 (C), and human CRBP1 (D). In each
case, [^3H]retinol was used as the radioligand. IC[50] values
were 90 nm for hRBP4 (n = 11 independent determinations), 66 nm
for mRBP4 (n = 4), and > 30 μm for hCRBP1 (n = 4). E,
concentration-response curves in the FRET assay. Retinol was
dosed in the presence of RBP4, TTR, and increasing
concentrations of A1120 (0–1 × 10^-5 m, as shown on the
right side). The K[i] of A1120 was 8.3 nm (n = 3).
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Figure 2.
Co-crystal structure of human RBP4 with A1120. A, overall
view of A1120-bound RBP4 structure. The RBP4 protein is shown in
schematic representation with a spectrum color from blue (N
terminus) to red (C terminus). A1120 is shown in stick
representation with magenta for carbon atoms, red for oxygen
atoms, blue for nitrogen atoms, and pale cyan for fluorine
atoms. The 2f[o] - f[c] electron density map, contoured at 1σ,
for A1120 is shown in gray mesh. B, protein-ligand interactions
for A1120. The protein is shown in both stick (spectrum color)
and molecular surface (wheat color) representations. The
hydrogen bonds between RBP4 and A1120 are shown as black dashed
lines. C, superposition of the A1120-RBP4 co-crystal structure
and retinol-RBP4 co-crystal structure (PDB code: 1RBP). The
carbon atoms are colored in gray for the retinol-bound
structure. D, superposition of the A1120-RBP4 co-crystal
structure on the RBP4·TTR complex structure (PDB code:
1QAB). The TTR tetramer is shown in molecule surface
representation. The RBP4 proteins are shown in schematic
representation with the RBP4 protein shown in gray in the TTR
complex and in spectrum color in the A1120-bound form.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
7673-7680)
copyright 2009.
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